Obesity is a rapidly advancing worldwide epidemic. Within the United States alone, 60% of the population is considered to be overweight. While new treatments for obesity have been introduced in the last decade, these drugs are only capable of reducing body weight by 10%, and patients typically gain back the lost weight following cessation of treatment. The potential for more effective therapeutics may be realized by targeting hormonal systems residing within the hypothalamus, a region of the brain critical for the appropriate regulation of food intake and energy utilization. Melanin concentrating hormone (MCH) is a prominent hormonal system originating within the lateral hypothalamus, which is responsible for initiating food intake. Genetically manipulating the expression of either the MCH ligand, or its receptor, inevitably results in alteration of body weight. Thus, mice overexpressing MCH ligand are obese, while mice lacking either the ligand or the receptor are lean. These data are consistent with the notion that blocking the interaction between MCH and its receptor will provide an effective means by which to reduce food intake in humans, and ultimately cause a loss of body weight. During the first phase of this project, we used high-throughput organic chemistry to develop multiple chemical series of potent MCH antagonists. We have also developed a number of critical in vitro and in vivo assays with which to monitor the bioavailability of these compounds, and their ability to inhibit acute food intake. In the second phase of this project, we propose to further refine these small molecules to improve their bioavailability. This will be accomplished by computer assisted drug design in conjunction with evaluation for a number of biological parameters including receptor affinity, hepatic stability, membrane permeability, and the potential for adverse reactions with liver enzymes necessary for proper drug metabolism. Compounds successfully emerging from this process will be further evaluated in acute and chronic feeding paradigms in order to select candidates suitable for clinical trials. [unreadable] [unreadable]